Nitrosated and nitrosylated compounds and compositions and their use for treating respiratory disorders

Abstract

Disclosed are (i) compounds of a steroid, a beta-agonist, an anticholinergic, a mast cell stabilizer and a phosphodiesterase (PDE) inhibitor directly or indirectly linked to a NO or NO2 group or a group which stimulates endogenous production of NO or EDRF in vivo; (ii) compositions of steroids, beta-agonists, anticholinergics, mast cell stabilizers and PDE inhibitors, which can optionally be substituted with at least one NO or NO2 moiety or a group which stimulates endogenous production of NO or EDRF in vivo, and a compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NO-), or as the neutral species, nitric oxide (NO.) or that stimulates endogenous production of NO or EDRF in vivo; and (iii) uses for them in preventing and/or treating respiratory disorders.

What is claimed is:  
     
       1. A composition comprising a compound of structure IA, IB or IC and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase, 
       wherein the compound of structure IA is:                    
       wherein 
       A is —CH═CH— or —CH 2 —CH 2 —;  
       R 1  is  
       (1) hydrogen; or  
       (2) —C(O)—CH 2 —S—D;  
       D is  
       (i) —NO or  
       (ii) —NO 2 ;  
       R 2  and R 3  are each independently hydrogen, hydroxyl, lower alkyl, —O(O)C—R i  or —S—R i , wherein R i  is hydrogen, lower alkyl or lower haloalkyl, or R 2  and R 3  taken together are                    
       and R 1   i  and R 2   i  are each independent R i ;  
       R 4  and R 5  are each independently hydrogen or halogen; and  
       R 6  is  
       (1) hydrogen;  
       (2) —NO;  
       (3) —NO 2 ; or  
       (4) —C(O)—CH 2 —B—D 1 ;  
       where B is oxygen or sulfur, and D 1  is hydrogen, —NO or —NO 2 ;  
       with the proviso that when R 1  is hydrogen, then R 6  is —NO, —NO 2  or —C(O)—CH 2 —B—D 1  where B is oxygen or sulfur and D 1  is —NO or —NO 2 ;  
       wherein the compound of structure IB is:                    
       wherein 
       A is —CH═CH— or —CH 2 —CH 2 —;  
       R 1  is  
       (1) hydrogen; or  
       (2) —C(O)—CH 2 —B—D 1 ;  
       B is oxygen or sulfur;  
       D 1  is  
       (i) hydrogen;  
       (ii) —NO; or  
       (iii) —NO 2 ;  
       R 2  and R 3  are each independently hydrogen, hydroxyl, lower alkyl, —O(O)C—R i  or —S—R i , wherein R i  is hydrogen, lower alkyl or lower haloalkyl, or R 2  and R 3  taken together are                    
       and R 1   i  and R 2   i  are each independent R i ;  
       R 4  and R 5  are each independently hydrogen or halogen; and  
       R 6  is —C(O)—CH 2 —B—D 1 ; where B is oxygen or sulfur, and D 1  is hydrogen, —NO or —NO 2 ;  
       with the proviso that when the D 1  group of R 6  is hydrogen, then R 1  is not hydrogen and the D 1  group of R 1  is not hydrogen;  
       wherein the compound of structure IC is:                    
       wherein 
       A is —CH═CH— or —CH 2 —CH 2 —;  
       R 1  is  
       (1) —C(O)—CH 2 —B—D 2 ;  
       (2) —C(O)—C(O)—O—R;  
       (3) —C(O)—B—R;  
       (4) —C(O)—CH 2 —B—C(O)—R;  
       (5) —C(O)—CH 2 —X;  
       (6) —S—R;  
       (7) —C(O)—CH 2 —B—M;  
        wherein  
       B is oxygen or sulfur; X is a halogen; R is hydrogen or lower alkyl;  
       D 2  is  
       (i) —CH(R d )—O—C(O)—Y—(C(R e )(R f )) p —T—Q;  
       (ii) —C(O)—T 1 —(C(R e )(R f )) p —T 2 —Q; or  
       (iii) —C(O)—T—(C(R y )(R z )) p H;  
        wherein  
       R d  is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl or heteroaryl; Y is oxygen, sulfur or NR i ; R i  is hydrogen, lower alkyl, lower haloalkyl or heteroaryl; R e  and R f  are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R e  and R f  taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; p is an integer from 1 to 6; T, T 1  and T 2  are each independently a covalent bond, oxygen, sulfur or nitrogen; Q is —NO or —NO 2 ; with the proviso that in “T—Q” and “T 2 —Q”, T and T 2  cannot be a covalent bond;  
       R y  and R z  are each independently —T 1 —(R e )(R f )) p —G—(C(R e )(R f )) p —T 2 —Q; wherein G is a covalent bond, —T—C(O)—, —C(O)—T or Y; wherein R d , R e , R f , p, Q, T, T 1 , T 2  and Y are as defined above; and  
       M is  
       (i) —C(O)—T—(C(R e )(R f )) p —G—(C(R e )(R f )) p —N(N—(O − )•N═O)—R i  or  
       (ii) —CH(R d )—O—C(O)—T—(C(R e )(R f )) p —G—(C(R e )(R f )) p —N(N—(O − )•N═O)—R i ;  
       wherein T, R e , R f , p, G, R i , and R d  are as defined above;  
       R 2  and R 3  are each independently hydrogen, hydroxyl, lower alkyl, —O(O)C—R i  or —S—R i , or R 2  and R 3  taken together are                    
       wherein R i  is as defined above, and R 1   i  and R 2   i  are each independent R i ;  
       R 4  and R 5  are each independently hydrogen or halogen; and  
       R 6  is hydrogen, D 2  or M; where D 2  and M are as defined above; with the proviso that R 6  must be D 2  or M if the substituent selected for R 1  does not include D 2  or M.  
     
     
       2. The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier or excipient. 
     
     
       3. The composition of  claim 1 , wherein R 1  is —C(O)—CH 2 —B—D 2 ; and D 2  is —CH(R d )—O—C(O)—Y—(C(R e )(R f )) p —T—Q; wherein B, R d , Y, R e , R f , p, T and Q are as defined in  claim 1 . 
     
     
       4. The composition of  claim 1 , wherein R 1  is —C(O)—CH 2 —B—D 2 ; and D 2  is —C(O)—T 1 —(C(R e )(R f )) p —T 2 —Q; wherein B, T 1 , R e , R f , p, T 2  and Q are as defined in  claim 1 . 
     
     
       5. The composition of  claim 1 , wherein R 1  is —C(O)—CH 2 —B—D 2 ; and D 2  is —C(O)—T—(C(R y )(R z )) p H; wherein B, T, R y , R z  and p are as defined in  claim 1 . 
     
     
       6. The composition of  claim 1 , wherein R 1  is hydrogen, or R 1  is —C(O)—CH 2 —S—D wherein D is —NO, and R 6  is —NO, —NO 2  or —C(O)—CH 2 —B—D 1 , wherein B is oxygen or sulfur and D 1  is —NO or —NO 2 . 
     
     
       7. The composition of  claim 1 , wherein the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase is an S-nitrosothiol. 
     
     
       8. The composition of  claim 7 , wherein the S-nitrosothiol is S-nitroso-N-acetylcysteine, S-nitroso-captopril, S-nitroso-homocysteine, S-nitroso-cysteine, or S-nitroso-glutathione. 
     
     
       9. The composition of  claim 7 , wherein the S-nitrosothiol is 
       (i) CH 3 (C(R e )(R f )) x SNO;  
       (ii) HS(C(R e )(R f )) x SNO;  
       (iii) ONS(C(R e )(R f )) x B; or  
       (iv) H 2 N—CH(CO 2 H)—(CH 2 ) x —C(O)NH—CH(CH 2 SNO)—C(O)NH—CH 2 —CO 2 H;  
       wherein x is 2 to 20; R e  and R f  are each independently hydrogen, lower alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R e  and R f  taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; and B is fluoro, C 1-6  alkoxy, cyano, carboxamido, cycloalkyl, arylalkoxy, alkylsulfinyl, arylthio, alkylamino, dialkylamino, hydroxy, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, amino, carboxyl, hydrogen, nitro or aryl.  
     
     
       10. The composition of  claim 1 , wherein the composition is in a form that can be administered by oral inhalation, nasal inhalation or intranasal mucosal administration. 
     
     
       11. The composition of  claim 1 , wherein the composition is in a form that can be administered as an aerosol. 
     
     
       12. The composition of  claim 1 , wherein the composition is in a form that can be administered orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously or subcutaneously. 
     
     
       13. The composition of  claim 1 , comprising the compound of structure IA and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase. 
     
     
       14. The composition of  claim 1 , comprising the compound of structure IB and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase. 
     
     
       15. The composition of  claim 1 , comprising the compound of structure IC and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase. 
     
     
       16. A method for treating asthma in an individual comprising administering a therapeutically effective amount of the composition of  claim 1 . 
     
     
       17. A method for treating a respiratory disorder in an individual comprising administering a therapeutically effective amount of the composition of  claim 11 . 
     
     
       18. The method of  claim 17 , wherein the respiratory disorder is acute pulmonary vasoconstriction, pneumonia, traumatic injury, aspiration or inhalation injury, fat embolism in the lung, acidosis, inflammation of the lung, adult respiratory distress syndrome, acute pulmonary edema, acute mountain sickness, asthma, post cardiac surgery, acute pulmonary hypertension, persistent pulmonary hypertension of the newborn, perinatal aspiration syndrome, hyaline membrane disease, acute pulmonary thromboembolism, heparin-protamine reactions, sepsis, status asthmaticus, hypoxia, chronic pulmonary hypertension, bronchopulmonary dysplasia, chronic pulmonary thromboembolism, idiopathic pulmonary hypertension, primary pulmonary hypertension or chronic hypoxia. 
     
     
       19. A method of treating cystic fibrosis in an individual comprising administering a therapeutically effective amount of the composition of  claim 1 . 
     
     
       20. The method of  claim 16 ,  17  or  19 , comprising administering a therapeutically effective amount of the composition by oral inhalation, by nasal inhalation, or by intranasal mucosal administration. 
     
     
       21. The method of  claim 16 ,  17  or  19 , comprising administering a therapeutically effective amount of the composition as an aerosol. 
     
     
       22. The method of  claim 16 ,  17  or  19 , comprising administering a therapeutically effective amount of the composition orally, enterally, topically, vaginally, sublingually, rectally, intramuscularly, intravenously, or subcutaneously. 
     
     
       23. A kit comprising the composition of  claim 1 . 
     
     
       24. A kit comprising a compound of structure IA, IB or IC and a compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase, 
       wherein the compound of structure IA is:                    
       wherein 
       A is —CH═CH— or —CH 2 —CH 2 —;  
       R 1  is  
       (1) hydrogen; or  
       (2) —C(O)—CH 2 —S—D;  
       D is  
       (i) —NO or  
       (ii) —NO 2 ;  
       R 2  and R 3  are each independently hydrogen, hydroxyl, lower alkyl, —O(O)C—R i  or —S—R i , wherein R i  is hydrogen, lower alkyl or lower haloalkyl, or R 2  and R 3  taken together are                    
       and R 1   i  and R 2   i  are each independent R i ;  
       R 4  and R 5  are each independently hydrogen or halogen; and  
       R 6  is  
       (1) hydrogen;  
       (2) —NO  
       (3) —NO 2 ; or  
       (4) —C(O)—CH 2 —B—D 1 ;  
       where B is oxygen or sulfur, and D 1  is hydrogen, —NO or —NO 2 ;  
       with the proviso that when R 1  is hydrogen, then R 6  is —NO, —NO 2  or —C(O)—CH 2 —B—D 1 , where B is oxygen or sulfur and D 1  is —NO or —NO 2 ;  
       wherein the compound of structure IB is:                    
       wherein 
       A is —CH═CH— or —CH 2 —CH 2 —;  
       R 1  is  
       (1) hydrogen; or  
       (2) —C(O)—CH 2 —B—D 1 ;  
       B is oxygen or sulfur;  
       D 1  is  
       (i) hydrogen;  
       (ii) —NO; or  
       (iii) —NO 2 ;  
       R 2  and R 3  are each independently hydrogen, hydroxyl, lower alkyl, —O(O)C—R i  or —S—R i , wherein R i  is hydrogen, lower alkyl or lower haloalkyl, or R 2  and R 3  taken together are                    
       and R 1   i  and R 2   i  are each independent R i ;  
       R 4  and R 5  are each independently hydrogen or halogen; and  
       R 6  is —C(O)—CH 2 —B—D 1 ; where B is oxygen or sulfur, and D 1  is hydrogen, —NO or —NO 2 ;  
       with the proviso that when the D 1  group of R 6  is hydrogen, then R 1  is not hydrogen and the D 1  group of R 1  is not hydrogen;  
       wherein the compound of structure IC is:                    
       wherein 
       A is —CH═CH— or —CH 2 —CH 2 —;  
       R 1  is  
       (1) —C(O)—CH 2 —B—D 2 ;  
       (2) —C(O)—C(O)—O—R;  
       (3) —C(O)—B—R;  
       (4) —C(O)—CH 2 —B—C(O)—R;  
       (5) —C(O)—CH 2 —X;  
       (6) —S—R;  
       (7) —C(O)—CH 2 —B—M;  
        wherein  
       B is oxygen or sulfur; X is a halogen; R is hydrogen or lower alkyl;  
       D 2  is  
       (i) —CH(R d )—O—C(O)—Y—(C(R e )(R f )) p —T—Q;  
       (ii) —C(O)—T 1 —(C(R e )(R f )) p —T 2 —Q; or  
       (iii) —C(O)—T—(C(R y )(R z )) p H;  
        wherein  
       R d  is hydrogen, lower alkyl, cycloalkyl, aryl, alkylaryl or heteroaryl; Y is oxygen, sulfur or NR i ; R i  is hydrogen, lower alkyl, lower haloalkyl or heteroaryl; R e  and R f  are each independently hydrogen, lower allyl, cycloalkyl, aryl, heteroaryl, arylalkyl, alkylamino, dialkylamino, or carboxy, or R e  and R f  taken together with the carbon atom to which they are attached are carbonyl, cycloalkyl or bridged cycloalkyl; p is an integer from 1 to 6; T, T 1  and T 2  are each independently a covalent bond, oxygen, sulfur or nitrogen; Q is —NO or —NO 2 ; with the proviso that in “T—Q” and “T 2 —Q”, T and T 2  cannot be a covalent bond;  
       R y  and R z  are each independently —T 1 —(C(R e )(R f )) p —G—(C(R e )(R f )) p —T 2 —Q; wherein G is a covalent bond, —T—C(O)—, —C(O)—T or Y; wherein R d , R e , R f , p, Q, T, T 1 , T 2  and Y are as defined above; and  
       M is  
       (i) —C(O)—T—(C(R e )(R f )) p —G—(C(R e )(R f )) p —N(N—(O − )•N═O)—R i  or  
       (ii) —CH(R d )—O—C(O)—T—(C(R e )(R f )) p —G—(C(R e )(R f )) p —N(N—(O − )•N═O)—R i ;  
       wherein T, R e , R f , p, G, R i , and R d  are as defined above;  
       R 2  and R 3  are each independently hydrogen, hydroxyl, lower alkyl, —O(O)C—R i  or —S—R i , or R 2  and R 3  taken together are                    
       wherein R i  is as defined above, and R 1   i  and R 2   i  are each independent R i ;  
       R 4  and R 5  are each independently hydrogen or halogen; and  
       R 6  is hydrogen, D 2  or M; where D 2  and M are as defined above; with the proviso that R 6  must be D 2  or M if the substituent selected for R 1  does not include D 2  or M.  
     
     
       25. The kit of  claim 24 , wherein the compound of structure IA, IB or IC and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase are separate components in the kit or are in the form of a composition in the kit. 
     
     
       26. The kit of  claim 24 , comprising the compound of structure IA and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase. 
     
     
       27. The kit of  claim 24 , comprising the compound of structure IB and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase. 
     
     
       28. The kit of  claim 24 , comprising the compound of structure IC and the compound that donates, transfers or releases nitric oxide, elevates endogenous synthesis levels of nitric oxide or endothelium-derived relaxing factor, or is a substrate for nitric oxide synthase.